Pharmaceutical composition containing a compound having a thrombopoietin receptor agonistic activity

ABSTRACT

The present inventor has found out that the following criteria enable to ensure an effect for increasing the platelet count while preventing an excessive increase in the platelet count; 
     “when the platelet count has increased by a certain amount and reached to a sufficient level of the platelet count during administration of a pharmaceutical composition containing a compound having a thrombopoietin receptor agonistic activity, administration of the pharmaceutical composition is discontinued thereafter”.

FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition containinga compound having a thrombopoietin receptor agonistic activity.

BACKGROUND OF THE INVENTION

Thrombocytopenia is a disease in which platelet destruction is promotedor platelets are insufficiently produced, causing a reduction in thenumber of platelets and resulting in bleeding tendency. Hemorrhagicevents include brain hemorrhage, internal hemorrhage, petechia, purpura,mucosal hemorrhages (nasal hemorrhage, gastrointestinal hemorrhage,genital hemorrhage) and the like, and in some cases, excessive bleedingmay be observed after surgery.

It is known that one of the causes of thrombocytopenia is chronic liverdisease. In chronic liver disease patients, a decrease in hepatic spareability with the development of disease stages, and a decrease in theplatelet count with hypersplenism are observed. Most of chronichepatitis is caused by hepatitis B or C virus infection, of whichhepatitis C virus infection is predominant. Hepatitis C tends to becomechronic and is developed to liver cirrhosis and further tohepatocellular carcinoma, causing about 34,000 deaths annually. Upontreatment for hepatitis or liver cancer, patients with thrombocytopeniamay not be able to receive anti-virus therapy using interferons or mayrequire splenectomy, partial splenic embolization (PSE) or platelettransfusion when undergoing invasive procedures such as laparotomy andlocal therapy.

However, these procedures have the following problems, and thus are notalways safe and convenient:

splenectomy is highly invasive and is reported to cause portal veinthrombosis and decrease immunocompetence;PSE is reported to cause splenic abscess and sepsis;platelet transfusion has risks of transfusion-related side effects(transfusion-related acute lung injury and infection), and plateletproducts have a short expiration date (4 days after blood collection).It is also known that repeated platelet transfusion may promote antibodyproduction, causing platelet transfusion refractoriness.

Under these circumstances, there is a need for a therapeutic agent forthrombocytopenia that has no side effect and can be readilyadministered.

Thrombopoietin (TPO) is a cytokine that acts on hematopoietic stemcells/megakaryocyte progenitor cells to promote proliferation anddifferentiation to megakaryocytes and production of platelets. Arecombinant human TPO was previously studied in a clinical trial.However, it induced a neutralizing antibody directed to endogenous TPO,and thus the development thereof was stopped due to antigenicity. Amongcytokines having activity on production of platelets in megakaryocytes,only an injection containing interleukin 11 is clinically applied in theUnited States. However, the approved indication thereof is limited toimprovement of thrombocytopenia caused by bone-marrow suppression afterchemotherapy because of side effects including fluid accumulation,palpitation, edema and the like.

A nucleotide sequence of a gene encoding the thrombopoietin receptor isdisclosed in Non-Patent Document 1.

Under these circumstances, compounds having a thrombopoietin receptoragonistic activity are expected as therapeutic agents forthrombocytopenia that can replace the present therapies and treatmentsincluding platelet transfusion. As therapeutic agents for chronic immunethrombocytopenia (chronic ITP), romiplostim which is an injectablethrombopoietin mimetic peptide and eltrombopag which is a low molecularTPO receptor agonist are currently approved in the United States andEurope.

Patent Document 1 discloses, as a compound having a thrombopoietinreceptor agonistic activity,(E)-3-[2,6-dichloro-4-[4-[3-[(S)-1-hexyloxyethyl]-2-methoxyphenyl]-thiazol-2-ylcarbamoyl]-phenyl]-2-methylacrylicacid.

Eltrombopag, a low molecular compound having a thrombopoietin receptoragonistic activity, was studied in a clinical trial abroad designed toadminister the investigational drug for 2 weeks before the invasiveprocedures to chronic liver disease patients who were scheduled toundergo invasive procedures and had a platelet count of less than5×10⁴/μL and the Child-Pugh score of 12 or less. The results showed thatan avoidance of platelet transfusion, an efficacy endpoint, was higherin the active drug group than in the placebo group (placebo group: 19%,active drug group: 72%). However, the incidence of portal veinthrombosis was higher in the active drug group than in the placebo group(placebo group: 1%, active drug group: 4%). It is reported in Non-PatentDocument 2 that most cases of portal vein thrombosis were developedafter invasive procedures carried out after termination ofadministration of the investigational drug and that the platelet countin 5 cases out of 6 in the active drug group was 20×10⁴/μL or higher atthe time of the development of portal vein thrombosis. With regard tothe correlation between the risk of development of portal veinthrombosis and the platelet count, the risk in the group having theplatelet count of 20×10⁴/μL or higher during the investigation periodwas about 9 times higher than the risk in the group with the plateletcount of less than 20×10⁴/μL (10.6% vs. 1.2%). Thus it is suggested thatan increase in the platelet count in patients having thrombocytopeniaresulting from development of chronic hepatitis to 20×10⁴/μL or highermay increase the risk of onset of portal vein thrombosis.

Compounds having a thrombopoietin receptor agonistic activity,eltrombopag and romiplostim, have already been launched for theindication of “chronic idiopathic thrombocytopenic purpura”. Theadministration discontinuating criteria of the drugs upon excessiveincrease in the platelet count indicated in the package inserts of thedrugs (Non-Patent Document 3 and 4) is “stop the drug if the plateletcount exceeds 400,000/μL”.

PRIOR ART REFERENCES [Patent Document 1]

-   International Publication WO 2009/017098

[Non-Patent Document 1]

-   Proceedings of the National Academy of Sciences of the United States    of America (Proc. Natl. Acad. Sci. USA) 1992, vol. 89, p. 5640-5644

[Non-Patent Document 2]

-   Ligand Pharmaceuticals, Inc., “Eltrombopag in Chronic Liver Disease    Patients with Thrombocytopenia Undergoing an Elective Invasive    Procedure: Results from ELEVATE, a Randomised Clinical Trial.”    <Internet URL:    http://phx.corporate-ir.net/External.File?item=UGFyZW50SUQ9NDMxMzY4fENoaWxkSUQ9NDQ5NjIwfFR5cGU9MQ==&t=1>

[Non-Patent Document 3]

-   A package insert of Romiplate (trade name) for subcutaneous    injection (250 μg; general name: romiplostim) (April 2011, version    1), Kyowa Hakko Kirin Co., Ltd.

[Non-Patent Document 4]

-   A package insert of Revolade (trade name) tablets (12.5 mg and 25    mg; general name: eltrombopag) (October 2010, version 1),    GlaxoSmithKline K.K.

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

It is difficult for conventional pharmaceutical compositions containinga compound having a thrombopoietin receptor agonistic activity to bothincrease the platelet count to a sufficient level and avoid an excessiveincrease in the platelet count.

Thus the purpose of the present invention is to provide a pharmaceuticalcomposition containing a compound having a thrombopoietin receptoragonistic activity that enable to both increase the platelet count to asufficient level and avoid an excessive increase in the platelet count.

Means for Solving the Problem

The present inventor has found out that the following criteria enable toensure an effect for increasing the platelet count while preventing anexcessive increase in the platelet count;

“when the platelet count has increased by a certain amount and hasreached to a sufficient level of the platelet count duringadministration of a pharmaceutical composition containing a compoundhaving a thrombopoietin receptor agonistic activity, administration ofthe pharmaceutical composition is discontinued thereafter”.

Thus the present invention relates to the following points:

(1) A pharmaceutical composition for increasing platelets containing acompound having a thrombopoietin receptor agonistic activity,characterized by discontinuing administration of the pharmaceuticalcomposition to a patient at the time point when a platelet count in thepatient has increased by 2×10⁴/μL or more from a platelet count beforeinitiation of administration and has reached to 5×10⁴/μL or higher.

(2) The pharmaceutical composition according to (1), which isadministered to a thrombocytopenia patient.

(3) The pharmaceutical composition according to (1) or (2), wherein theplatelet count in the patient before initiation of administration of thepharmaceutical composition is less than 5×10⁴/μL.

(4) The pharmaceutical composition according to (2) or (3), wherein thepatient is scheduled to undergo invasive procedures.

(5) The pharmaceutical composition according to (4), wherein theinvasive procedures are elective invasive procedures.

(6) The pharmaceutical composition according to (4) or (5), wherein theinvasive procedures are radiofrequency ablation.

(7) The pharmaceutical composition according to (6), wherein theradiofrequency ablation is performed on liver cancer.

(8) The pharmaceutical composition according to (7), wherein the livercancer is primary liver cancer.

(9) The pharmaceutical composition according to any of (1) to (8),wherein the patient has chronic liver disease.

(10) The pharmaceutical composition according to (9), wherein thechronic liver disease is caused by hepatitis B virus or hepatitis Cvirus.

(11) The pharmaceutical composition according to any of (1) to (10),wherein the compound having a thrombopoietin receptor agonistic activityis(E)-3-[2,6-dichloro-4-[4-[3-[(S)-1-hexyloxyethyl]-2-methoxyphenyl]-thiazol-2-ylcarbamoyl]-phenyl]-2-methylacrylicacid or a salt thereof.

(12) The pharmaceutical composition according to (11), which is orallyadministered.

(13) The pharmaceutical composition according to (12), which isadministered at 2.0 to 4.0 mg/day as an amount of(E)-3-[2,6-dichloro-4-[4-[3-[(S)-1-hexyloxyethyl]-2-methoxyphenyl]-thiazol-2-ylcarbamoyl]-phenyl]-2-methylacrylicacid or a salt thereof.

(14) The pharmaceutical composition according to (13), wherein a maximumadministration period with once daily administration is 14 days or less.

(15) The pharmaceutical composition according to (1), for promotingproduction of platelets before invasive procedures in thrombocytopenicpatients with chronic liver disease.

(16) The pharmaceutical composition according to (1), for promotingproduction of platelets before elective invasive procedures inthrombocytopenic patients with chronic liver disease.

(17) The pharmaceutical composition according to (1), for promotingproduction of platelets before local therapy for primary liver cancer.

(18) The pharmaceutical composition according to (1), for promotingproduction of platelets before radiofrequency ablation for primary livercancer.

(19) The pharmaceutical composition according to (1), for promotingproduction of platelets before various minimally invasive procedures inthrombocytopenic patients with chronic liver disease.

(20) A method for increasing platelets comprising the steps of:

administering a pharmaceutical composition containing a compound havinga thrombopoietin receptor agonistic activity to a patient; and

discontinuing administration at the time point when a platelet count inthe patient has increased by 2×10⁴/μL or more from a platelet countbefore initiation of administration and has reached to 5×10⁴/μL orhigher.

(21) Use of a compound having a thrombopoietin receptor agonisticactivity for increasing platelets, characterized by discontinuingadministration of the compound to a patient at the time point when aplatelet count in the patient has increased by 2×10⁴/μL or more from aplatelet count before initiation of administration and has reached to5×10⁴/μL or higher.

(1A) A method for increasing platelets comprising the steps of:

administering a pharmaceutical composition containing a compound havinga thrombopoietin receptor agonistic activity to a patient; and

discontinuing administration at the time point when a platelet count inthe patient has increased by 2×10⁴/μL or more from a platelet countbefore initiation of administration and has reached to 5×10⁴/μL orhigher.

(2A) The method for increasing platelets according to (1A), wherein thepatient has thrombocytopenia.

(3A) The method for increasing platelets according to (1A) or (2A),wherein the platelet count in the patient before initiation ofadministration of the pharmaceutical composition is less than 5×10⁴/μL.

(4A) The method for increasing platelets according to (2A) or (3A),wherein the patient is scheduled to undergo invasive procedures.

(5A) The method for increasing platelets according to (4A), wherein theinvasive procedures are elective invasive procedures.

(6A) The method for increasing platelets according to (4A) or (5A),wherein the invasive procedures are radiofrequency ablation.

(7A) The method for increasing platelets according to (6A), wherein theradiofrequency ablation is performed on liver cancer.

(8A) The method for increasing platelets according to (7A), wherein theliver cancer is primary liver cancer.

(9A) The method for increasing platelets according to any of (1A) to(8A), wherein the patient has chronic liver disease.

(10A) The method for increasing platelets according to (9A), wherein thechronic liver disease is caused by hepatitis B virus or hepatitis Cvirus.

(11A) The method for increasing platelets according to any of (1A) to(10A), wherein the compound having a thrombopoietin receptor agonisticactivity is(E)-3-[2,6-dichloro-4-[4-[3-[(S)-1-hexyloxyethyl]-2-methoxyphenyl]-thiazol-2-ylcarbamoyl]-phenyl]-2-methylacrylicacid or a salt thereof.

(12A) The method for increasing platelets according to (11A), whereinthe pharmaceutical composition is orally administered.

(13A) The method for increasing platelets according to (12A), whereinthe pharmaceutical composition is administered at 2.0 to 4.0 mg/day asan amount of(E)-3-[2,6-dichloro-4-[4-[3-[(S)-1-hexyloxyethyl]-2-methoxyphenyl]-thiazol-2-ylcarbamoyl]-phenyl]-2-methylacrylicacid or a salt thereof.

(14A) The method for increasing platelets according to (13A), wherein amaximum administration period with once daily administration is 14 daysor less.

(15A) The method for increasing platelets according to (1A), forpromoting production of platelets before invasive procedures inthrombocytopenic patients with chronic liver disease.

(16A) The method for increasing platelets according to (1A), forpromoting production of platelets before elective invasive procedures inthrombocytopenic patients with chronic liver disease.

(17A) The method for increasing platelets according to (1A), forpromoting production of platelets before local therapy for primary livercancer.

(18A) The method for increasing platelets according to (1A), forpromoting production of platelets before radiofrequency ablation forprimary liver cancer.

(19A) The method for increasing platelets according to (1A), forpromoting production of platelets before various minimally invasiveprocedures in thrombocytopenic patients with chronic liver disease.

(1B) A compound having a thrombopoietin receptor agonistic activity foruse in increasing platelets, characterized by discontinuingadministration of the compound to a patient at the time point when aplatelet count in the patient has increased by 2×10⁴/μL or more from aplatelet count before initiation of administration and has reached to5×10⁴/μL or higher.

(2B) The compound according to (1B), which is administered to athrombocytopenia patient.

(3B) The compound according to (1B) or (2B), wherein the platelet countin the patient before initiation of administration of the compound isless than 5×10⁴/μL.

(4B) The compound according to (2B) or (3B), wherein the patient isscheduled to undergo invasive procedures.

(5B) The compound according to (4B), wherein the invasive procedures areelective invasive procedures.

(6B) The compound according to (4B) or (5B), wherein the invasiveprocedures are radiofrequency ablation.

(7B) The compound according to (6B), wherein the radiofrequency ablationis performed on liver cancer.

(8B) The compound according to (7B), wherein the liver cancer is primaryliver cancer.

(9B) The compound according to any of (1B) to (8B), wherein the patienthas chronic liver disease.

(10B) The compound according to (9B), wherein the chronic liver diseaseis caused by hepatitis B virus or hepatitis C virus.

(11B) The compound according to any of (1B) to (10B), wherein thecompound having a thrombopoietin receptor agonistic activity is(E)-3-[2,6-dichloro-4-[4-[3-[(S)-1-hexyloxyethyl]-2-methoxyphenyl]-thiazol-2-ylcarbamoyl]-phenyl]-2-methylacrylicacid or a salt thereof.

(12B) The compound according to (11B), which is orally administered.

(13B) The compound according to (12B), which is administered at 2.0 to4.0 mg/day as an amount of(E)-3-[2,6-dichloro-4-[4-[3-[(S)-1-hexyloxyethyl]-2-methoxyphenyl]-thiazol-2-ylcarbamoyl]-phenyl]-2-methylacrylicacid or a salt thereof.

(14B) The compound according to (13B), wherein a maximum administrationperiod with once daily administration is 14 days or less.

(15B) The compound according to (1B), for promoting production ofplatelets before invasive procedures in thrombocytopenic patients withchronic liver disease.

(16B) The compound according to (1B), for promoting production ofplatelets before elective invasive procedures in thrombocytopenicpatients with chronic liver disease.

(17B) The compound according to (1B), for promoting production ofplatelets before local therapy for primary liver cancer.

(18B) The compound according to (1B), for promoting production ofplatelets before radiofrequency ablation for primary liver cancer.

(19B) The compound according to (1B), for promoting production ofplatelets before various minimally invasive procedures inthrombocytopenic patients with chronic liver disease.

(1C) Use of a compound having a thrombopoietin receptor agonisticactivity for manufacturing a medicament for increasing platelets,characterized by discontinuing administration of the medicament to apatient at the time point when a platelet count in the patient hasincreased by 2×10⁴/μL or more from a platelet count before initiation ofadministration and has reached to 5×10⁴/μL or higher.

(2C) Use of a compound according to (1C), wherein the medicament isadministered to a thrombocytopenia patient.

(3C) Use of a compound according to (1C) or (2C), wherein the plateletcount in the patient before initiation of administration of themedicament is less than 5×10⁴/μL.

(4C) Use of a compound according to (2C) or (3C), wherein the patient isscheduled to undergo invasive procedures.

(5C) Use of a compound according to (4C), wherein the invasiveprocedures are elective invasive procedures.

(6C) Use of a compound according to (4C) or (5C), wherein the invasiveprocedures are radiofrequency ablation.

(7C) Use of a compound according to (6C), wherein the radiofrequencyablation is performed on liver cancer.

(8C) Use of a compound according to (7C), wherein the liver cancer isprimary liver cancer.

(9C) Use of a compound according to any of (1C) to (8C), wherein thepatient has chronic liver disease.

(10C) Use of a compound according to (9C), wherein the chronic liverdisease is caused by hepatitis B virus or hepatitis C virus.

(11C) Use of a compound according to any of (1C) to (10C), wherein thecompound having a thrombopoietin receptor agonistic activity is(E)-3-[2,6-dichloro-4-[4-[3-[(S)-1-hexyloxyethyl]-2-methoxyphenyl]-thiazol-2-ylcarbamoyl]-phenyl]-2-methylacrylicacid or a salt thereof.

(12C) Use of a compound according to (11C), wherein the medicament isorally administered.

(13C) Use of a compound according to (12C), wherein the medicament isadministered at 2.0 to 4.0 mg/day as an amount of(E)-3-[2,6-dichloro-4-[4-[3-[(S)-1-hexyloxyethyl]-2-methoxyphenyl]-thiazol-2-ylcarbamoyl]-phenyl]-2-methylacrylicacid or a salt thereof.

(14C) Use of a compound according to (13C), wherein a maximumadministration period with once daily administration is 14 days or less.

(15C) Use of a compound according to (1C), for promoting production ofplatelets before invasive procedures in thrombocytopenic patients withchronic liver disease.

(16C) Use of a compound according to (1C), for promoting production ofplatelets before elective invasive procedures in thrombocytopenicpatients with chronic liver disease.

(17C) Use of a compound according to (1C), for promoting production ofplatelets before local therapy for primary liver cancer.

(18C) Use of a compound according to (1C), for promoting production ofplatelets before radiofrequency ablation for primary liver cancer.

(19C) Use of a compound according to (1C), for promoting production ofplatelets before various minimally invasive procedures inthrombocytopenic patients with chronic liver disease.

The present invention further includes the following embodiments of theabove points (1) to (21), (1A) to (19A), (1B) to (19B) and (1C) to(19C), wherein “2×10⁴/μL” and “5×10⁴/μL” are regarded as “a pre-definedlevel of platelet count increment” and “a pre-defined level of plateletcount”, respectively:

(1′) A pharmaceutical composition for increasing platelets containing acompound having a thrombopoietin receptor agonistic activity,

discontinuing administration of the pharmaceutical composition to apatient at the time point when a platelet count in the patient hasincreased by a pre-defined level of platelet count increment or morefrom a platelet count before initiation of administration and hasreached to a pre-defined level of platelet count or higher.

(2′) The pharmaceutical composition according to (1′), which isadministered to a thrombocytopenia patient.

(3′) The pharmaceutical composition according to (1′) or (2′), whereinthe platelet count in the patient before initiation of administration ofthe pharmaceutical composition is less than the pre-defined level ofplatelet count.

(4′) The pharmaceutical composition according to (2′) or (3′), whereinthe patient is scheduled to undergo invasive procedures.

(5′) The pharmaceutical composition according to (4′), wherein theinvasive procedures are elective invasive procedures.

(6′) The pharmaceutical composition according to (4′) or (5′), whereinthe invasive procedures are radiofrequency ablation.

(7′) The pharmaceutical composition according to (6′), wherein theradiofrequency ablation is performed on liver cancer.

(8′) The pharmaceutical composition according to (7′), wherein the livercancer is primary liver cancer.

(9′) The pharmaceutical composition according to any of (1′) to (8′),wherein the patient has chronic liver disease.

(10′) The pharmaceutical composition according to (9′), wherein thechronic liver disease is caused by hepatitis B virus or hepatitis Cvirus.

(11′) The pharmaceutical composition according to any of (1′) to (10′),wherein the compound having a thrombopoietin receptor agonistic activityis(E)-3-[2,6-dichloro-4-[4-[3-[(S)-1-hexyloxyethyl]-2-methoxyphenyl]-thiazol-2-ylcarbamoyl]-phenyl]-2-methylacrylicacid or a salt thereof.

(12′) The pharmaceutical composition according to (11′), which is orallyadministered.

(13′) The pharmaceutical composition according to (12′), which isadministered at 2.0 to 4.0 mg/day as an amount of(E)-3-[2,6-dichloro-4-[4-[3-[(S)-1-hexyloxyethyl]-2-methoxyphenyl]-thiazol-2-ylcarbamoyl]-phenyl]-2-methylacrylicacid or a salt thereof.

(14′) The pharmaceutical composition according to (13′), wherein amaximum administration period with once daily administration is 14 daysor less.

(15′) The pharmaceutical composition according to (1′), for promotingproduction of platelets before invasive procedures in thrombocytopenicpatients with chronic liver disease.

(16′) The pharmaceutical composition according to (1′), for promotingproduction of platelets before elective invasive procedures inthrombocytopenic patients with chronic liver disease.

(17′) The pharmaceutical composition according to (1′), for promotingproduction of platelets before local therapy for primary liver cancer.

(18′) The pharmaceutical composition according to (1′), for promotingproduction of platelets before radiofrequency ablation for primary livercancer.

(19′) The pharmaceutical composition according to (1′), for promotingproduction of platelets before various minimally invasive procedures inthrombocytopenic patients with chronic liver disease.

(20′) A method for increasing platelets comprising the steps of:

administering a pharmaceutical composition containing a compound havinga thrombopoietin receptor agonistic activity to a patient; and

discontinuing administration at the time point when a platelet count inthe patient has increased by a pre-defined level of platelet countincrement or more from a platelet count before initiation ofadministration and has reached to a pre-defined level of platelet countor higher.

(21′) Use of a compound having a thrombopoietin receptor agonisticactivity for increasing platelets, characterized by discontinuingadministration of the compound to a patient at the time point when aplatelet count in the patient has increased by a pre-defined level ofplatelet count increment or more from a platelet count before initiationof administration and has reached to a pre-defined level of plateletcount or higher.

(1A′) A method for increasing platelets comprising the steps of:

administering a pharmaceutical composition containing a compound havinga thrombopoietin receptor agonistic activity to a patient; and

discontinuing administration at the time point when a platelet count inthe patient has increased by a pre-defined level of platelet countincrement or more from a platelet count before initiation ofadministration and has reached to a pre-defined level of platelet countor higher.

(2A′) The method for increasing platelets according to (1A′), whereinthe patient has thrombocytopenia.

(3A′) The method for increasing platelets according to (1A′) or (2A′),wherein the platelet count in the patient before initiation ofadministration of the pharmaceutical composition is less than thepre-defined level of platelet count.

(4A′) The method for increasing platelets according to (2A′) or (3A′),wherein the patient is scheduled to undergo invasive procedures.

(5A′) The method for increasing platelets according to (4A′), whereinthe invasive procedures are elective invasive procedures.

(6A′) The method for increasing platelets according to (4A′) or (5A′),wherein the invasive procedures are radiofrequency ablation.

(7A′) The method for increasing platelets according to (6A′), whereinthe radiofrequency ablation is performed on liver cancer.

(8A′) The method for increasing platelets according to (7A′), whereinthe liver cancer is primary liver cancer.

(9A′) The method for increasing platelets according to any of (1A′) to(8A′), wherein the patient has chronic liver disease.

(10A′) The method for increasing platelets according to (9A′), whereinthe chronic liver disease is caused by hepatitis B virus or hepatitis Cvirus.

(11A′) The method for increasing platelets according to any of (1A′) to(10A′), wherein the compound having a thrombopoietin receptor agonisticactivity is(E)-3-[2,6-dichloro-4-[4-[3-[(S)-1-hexyloxyethyl]-2-methoxyphenyl]-thiazol-2-ylcarbamoyl]-phenyl]-2-methylacrylicacid or a salt thereof.

(12A′) The method for increasing platelets according to (11A′), whereinthe pharmaceutical composition is orally administered.

(13A′) The method for increasing platelets according to (12A′), whereinthe pharmaceutical composition is administered at 2.0 to 4.0 mg/day asan amount of(E)-3-[2,6-dichloro-4-[4-[3-[(S)-1-hexyloxyethyl]-2-methoxyphenyl]-thiazol-2-ylcarbamoyl]-phenyl]-2-methylacrylicacid or a salt thereof.

(14A′) The method for increasing platelets according to (13A), wherein amaximum administration period with once daily administration is 14 daysor less.

(15A′) The method for increasing platelets according to (1A′), forpromoting production of platelets before invasive procedures inthrombocytopenic patients with chronic liver disease.

(16A′) The method for increasing platelets according to (1A′), forpromoting production of platelets before elective invasive procedures inthrombocytopenic patients with chronic liver disease.

(17A′) The method for increasing platelets according to (1A′), forpromoting production of platelets before local therapy for primary livercancer.

(18A′) The method for increasing platelets according to (1A′), forpromoting production of platelets before radiofrequency ablation forprimary liver cancer.

(19A′) The method for increasing platelets according to (1A′), forpromoting production of platelets before various minimally invasiveprocedures in thrombocytopenic patients with chronic liver disease.

(1B′) A compound having a thrombopoietin receptor agonistic activity foruse in increasing platelets, characterized by discontinuingadministration of the compound to a patient at the time point when aplatelet count in the patient has increased by a pre-defined level ofplatelet count increment or more from a platelet count before initiationof administration and has reached to a pre-defined level of plateletcount or higher.

(2B′) The compound according to (1B′), which is administered to athrombocytopenia patient.

(3B′) The compound according to (1B′) or (2B′), wherein the plateletcount in the patient before initiation of administration of the compoundis less than the pre-defined level of platelet count.

(4B′) The compound according to (2B′) or (3B′), wherein the patient isscheduled to undergo invasive procedures.

(5B′) The compound according to (4B′), wherein the invasive proceduresare elective invasive procedures.

(6B′) The compound according to (4B′) or (5B′), wherein the invasiveprocedures are radiofrequency ablation.

(7B′) The compound according to (6B′), wherein the radiofrequencyablation is performed on liver cancer.

(8B′) The compound according to (7B′), wherein the liver cancer isprimary liver cancer.

(9B′) The compound according to any of (1B′) to (8B′), wherein thepatient has chronic liver disease.

(10B′) The compound according to (9B′), wherein the chronic liverdisease is caused by hepatitis B virus or hepatitis C virus.

(11B′) The compound according to any of (1B′) to (10B′), wherein thecompound having a thrombopoietin receptor agonistic activity is(E)-3-[2,6-dichloro-4-[4-[3-[(S)-1-hexyloxyethyl]-2-methoxyphenyl]-thiazol-2-ylcarbamoyl]-phenyl]-2-methylacrylicacid or a salt thereof.

(12B′) The compound according to (11B′), which is orally administered.

(13B′) The compound according to (12B′), which is administered at 2.0 to4.0 mg/day as an amount of(E)-3-[2,6-dichloro-4-[4-[3-[(S)-1-hexyloxyethyl]-2-methoxyphenyl]-thiazol-2-ylcarbamoyl]-phenyl]-2-methylacrylicacid or a salt thereof.

(14B′) The compound according to (13B′), wherein a maximumadministration period with once daily administration is 14 days or less.

(15B′) The compound according to (1B′), for promoting production ofplatelets before invasive procedures in thrombocytopenic patients withchronic liver disease.

(16B′) The compound according to (1B′), for promoting production ofplatelets before elective invasive procedures in thrombocytopenicpatients with chronic liver disease.

(17B′) The compound according to (1B′), for promoting production ofplatelets before local therapy for primary liver cancer.

(18B′) The compound according to (1B′), for promoting production ofplatelets before radiofrequency ablation for primary liver cancer.

(19B′) The compound according to (1B′), for promoting production ofplatelets before various minimally invasive procedures inthrombocytopenic patients with chronic liver disease.

(1C) Use of a compound having a thrombopoietin receptor agonisticactivity for manufacturing a medicament for increasing platelets,characterized by discontinuing administration of the medicament to apatient at the time point when a platelet count in the patient hasincreased by a pre-defined level of platelet count increment or morefrom a platelet count before initiation of administration and hasreached to a pre-defined level of platelet count or higher.

(2C′) Use of a compound according to (1C′), wherein the medicament isadministered to a thrombocytopenia patient.

(3C′) Use of a compound according to (1C′) or (2C′), wherein theplatelet count in the patient before initiation of administration of themedicament is less than the pre-defined level of platelet count.

(4C′) Use of a compound according to (2C′) or (3C′), wherein the patientis scheduled to undergo invasive procedures.

(5C′) Use of a compound according to (4C′), wherein the invasiveprocedures are elective invasive procedures.

(6C′) Use of a compound according to (4C′) or (5C′), wherein theinvasive procedures are radiofrequency ablation.

(7C′) Use of a compound according to (6C′), wherein the radiofrequencyablation is performed on liver cancer.

(8C′) Use of a compound according to (7C′), wherein the liver cancer isprimary liver cancer.

(9C′) Use of a compound according to any of (1C′) to (8C′), wherein thepatient has chronic liver disease.

(10C′) Use of a compound according to (9C′), wherein the chronic liverdisease is caused by hepatitis B virus or hepatitis C virus.

(11C′) Use of a compound according to any of (10′) to (10C′), whereinthe compound having a thrombopoietin receptor agonistic activity is(E)-3-[2,6-dichloro-4-[4-[3-[(S)-1-hexyloxyethyl]-2-methoxyphenyl]-thiazol-2-ylcarbamoyl]-phenyl]-2-methylacrylicacid or a salt thereof.

(12C′) Use of a compound according to (11C′), wherein the medicament isorally administered.

(13C′) Use of a compound according to (12C′), wherein the medicament isadministered at 2.0 to 4.0 mg/day as an amount of(E)-3-[2,6-dichloro-4-[4-[3-[(S)-1-hexyloxyethyl]-2-methoxyphenyl]-thiazol-2-ylcarbamoyl]-phenyl]-2-methylacrylicacid or a salt thereof.

(14C′) Use of a compound according to (13C′), wherein a maximumadministration period with once daily administration is 14 days or less.

(15C′) Use of a compound according to (1C′), for promoting production ofplatelets before invasive procedures in thrombocytopenic patients withchronic liver disease.

(16C′) Use of a compound according to (1C′), for promoting production ofplatelets before elective invasive procedures in thrombocytopenicpatients with chronic liver disease.

(17C′) Use of a compound according to (1C′), for promoting production ofplatelets before local therapy for primary liver cancer.

(18C′) Use of a compound according to (1C′), for promoting production ofplatelets before radiofrequency ablation for primary liver cancer.

(19C′) Use of a compound according to (1C′), for promoting production ofplatelets before various minimally invasive procedures inthrombocytopenic patients with chronic liver disease.

Effect of the Invention

The pharmaceutical composition having a thrombopoietin receptoragonistic activity according to the present invention is useful becauseit can increase platelets while avoiding a risk of thrombosis due to anexcessive increase in the platelet count.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustrative figure showing a schematic view of a PK/PDmodel with the mass balance equation thereof;

FIG. 2 shows the time course of the platelet count in each patientreceiving 2 mg/day of lusutrombopag (n=12). The y-axis shows theplatelet count (×10⁴/μL), and the x-axis shows the number of days afterinitiation of administration. Pre means day 1 of administration, and forexample D3 means day 3 of administration. The solid line shows theprofile of the platelet count during administration of lusutrombopag,and the dotted line shows the profile of the platelet count aftertermination of administration. For example, when the platelet count,which is measured before administration in day 3, reached theadministration discontinuating criteria and thus administration wasdiscontinued, the result is shown with the solid line until D3 and withthe dotted line at or after D3. When the platelet count did not reach tothe administration discontinuating criteria until day 7 ofadministration, the result is shown with the solid line until D8 andwith the dotted line at or after D8. The symbol x indicates the timepoint when the platelet transfusion was carried out and the studythereafter was discontinued in the patient (Example 2);

FIG. 3 shows the time course of the platelet count in each patientreceiving 2.5 mg/day of lusutrombopag (n=6). The y-axis shows theplatelet count (×10⁴/μL), and the x-axis shows the number of days afterinitiation of administration. Pre means day 1 of administration, and forexample D3 means day 3 of administration. The solid line shows theprofile of the platelet count during administration of lusutrombopag,and the dotted line shows the profile of the platelet count aftertermination of administration. For example, when the platelet count,which is measured before administration in day 3, reached theadministration discontinuating criteria and thus administration wasdiscontinued, the result is shown with the solid line until D3 and withthe dotted line at or after D3. When the platelet count did not reach tothe administration discontinuating criteria until day 7 ofadministration, the result is shown with the solid line until D8 andwith the dotted line at or after D8. The symbol x indicates the timepoint when the platelet transfusion was carried out and the studythereafter was discontinued in the patient (Example 2);

FIG. 4 shows the time course of the platelet count in each patientreceiving 3 mg/day of lusutrombopag (n=7). The y-axis shows the plateletcount (×10⁴/μL), and the x-axis shows the number of days afterinitiation of administration. Pre means day 1 of administration, and forexample D3 means day 3 of administration. The solid line shows theprofile of the platelet count during administration of lusutrombopag andthe dotted line shows the profile of the platelet count aftertermination of administration. For example, when the platelet count,which is measured before administration in day 3, reached theadministration discontinuating criteria and thus administration wasdiscontinued, the result is shown with the solid line until D3 and withthe dotted line at or after D3. When the platelet count did not reach tothe administration discontinuating criteria until day 7 ofadministration, the result is shown with the solid line until D8 andwith the dotted line at or after D8. The symbol x indicates the timepoint when the platelet transfusion was carried out and the studythereafter was discontinued (Example 2); and

FIG. 5 shows the time course of the platelet count in each patientreceiving 4 mg/day of lusutrombopag (n=8). The y-axis shows the plateletcount (×10⁴/μL), and the x-axis shows the number of days afterinitiation of administration. Pre means day 1 of administration, and forexample D3 means day 3 of administration. The solid line shows theprofile of the platelet count during administration of lusutrombopag,and the dotted line shows the profile of the platelet count aftertermination of administration. For example, when the platelet count,which is measured before administration in day 3, reached theadministration discontinuating criteria and thus administration wasdiscontinued, the result is shown with the solid line until D3 and withthe dotted line at or after D3. When the platelet count did not reach tothe administration discontinuating criteria until day 7 ofadministration, the result is shown with the solid line until D8 andwith the dotted line at or after D8. The symbol x indicates the timepoint when the platelet transfusion was carried out and the studythereafter was discontinued (Example 2).

MODE FOR CARRYING OUT THE INVENTION

The meanings of the terms used in the present specification aredescribed hereinafter. Each term has the same meaning when it is usedalone or in combination with other terms unless otherwise stated.

The term “thrombopoietin receptor agonistic activity” means a functionthat the object has an affinity towards the thrombopoietin receptor andthe substance acts like thrombopoietin.

A compound having a thrombopoietin receptor agonistic activity includesa low molecular compound and protein having a thrombopoietin receptoragonistic activity. Any compound having a thrombopoietin receptoragonistic activity, its pharmaceutically acceptable salt or a solvatethereof can be widely used. The following examples are not intended tolimit the compounds. The compounds include compounds disclosed in JP-ANo. H10-72492, International Publication WO 96/40750, JP-A No. H11-1477,JP-A No. H11-152276, International Publication WO 00/35446, JP-A No.H10-287634, International Publication WO 01/07423, InternationalPublication WO 01/53267, International Publication WO 02/059099,International Publication WO 02/059100, International Publication WO02/062775, International Publication WO 2003/062233, InternationalPublication WO 2004/029049, International Publication WO 2005/007651,International Publication WO 2005/014561, JP-A No. 2005-47905, JP-A No.2006-219480, JP-A No. 2006-219481, International Publication WO2007/004038, International Publication WO 2007/036709, InternationalPublication WO 2007/054783, International Publication WO 2009/017098 andthe like. More specifically, the compound includes lusutrombopag,eltrombopag, avatrombopag, totrombopag and romiplostim. Lusutrombopag,its pharmaceutically acceptable salt or a solvate thereof isparticularly preferred and lusutrombopag is still more preferred.

Lusutrombopag is a low molecular human thrombopoietin receptor agonist.The chemical formula of lusutrombopag is“(E)-3-[2,6-dichloro-4-[4-[3-[(S)-1-hexyloxyethyl]-2-methoxyphenyl]-thiazol-2-ylcarbamoyl]-phenyl]-2-methylacrylicacid”. Lusutrombopag is represented by the following chemical structuralformula:

Eltrombopag is represented by the following chemical structural formula:

Avatrombopag is represented by the following chemical structuralformula:

Totrombopag choline is represented by the following chemical structuralformula:

Romiplostim is a recombinant Fc-peptide fusion protein and includes theFc region of human IgG1 from positions 2 to 228 in the amino acidsequence thereof and a human thrombopoietin receptor-binding sequencefrom positions 229 to 269. However, it does not have homology with theendogenous thrombopoietin. Romiplostim is a protein composed of twosubunit each consisting of 269 amino acids.

Thrombocytopenia means a condition in which the number of platelets isdecreased. A patient with thrombocytopenia means a patient havingthrombocytopenia.

A pharmaceutical composition according to the present invention is amedicament for increasing platelets containing a compound having athrombopoietin receptor agonistic activity, and is characterized bydiscontinuing administration of the pharmaceutical composition to apatient at the time point when the platelet count in the patient hasincreased by 2×10⁴/μL or more from the platelet count before initiationof administration and has reached to 5×10⁴/μL or higher.

Prior to initiation of administration of a pharmaceutical composition ofthe present invention, the platelet count in a patient is measured. Theplatelet count in a patient is measured over time after initiation ofadministration.

The phrase “a platelet count in the patient has increased by 2×10⁴/μL ormore from a platelet count before initiation of administration and hasreached to 5×10⁴/μL or higher” means the situation that the plateletcount at a certain time point after initiation of administration hasincreased by 2×10⁴/μL or more from the platelet count before initiationof administration and the platelet count at the same time point hasreached to 5×10⁴/μL or higher.

The term “platelet count before initiation of administration” means theplatelet count before the first administration of a pharmaceuticalcomposition of the present invention. It is desirable to determine the“platelet count before initiation of administration” within a shortperiod before initiation of administration. For example, it ispreferably determined within 7 days before initiation of administrationand more preferably just before initiation of administration.

After initiation of administration, the platelet count is determinedover time after a certain period of time from initiation ofadministration. For example, the platelet count may be determined overtime after 3 days from initiation of administration.

The phrase “administration was discontinued” means that, administrationof a pharmaceutical composition of the present invention is stopped,when it is confirmed that the platelet count in the patient increase by2×10⁴/μL or more from a platelet count before initiation ofadministration and reach 5×10⁴/μL or higher in a determination of theplatelet count after initiation of administration.

The term “maximum administration period” means a maximum period of timeduring which a pharmaceutical composition of the present invention isadministered. For example, the maximum administration period of 7 daysmeans that administration is carried out for 7 days to a patient whodoes not reach to the administration discontinuating criteria, andadministration is discontinued at the time point to the patient whoreaches the administration discontinuating criteria. The maximumadministration period is preferably 14 days or less, more preferably 6to 10 days and most preferably 7 days.

The term “pre-defined level of platelet count” in the presentspecification means a reference value of the platelet count that isrequired before an invasive procedure. If the platelet count is lessthan the pre-defined level of platelet count, treatment is required forincreasing platelets such as platelet transfusion before carrying outinvasive procedures in order to avoid the risk of bleeding. “5×10⁴/μL”used in the administration discontinuating criteria is an embodiment ofthe “pre-defined level of platelet count”. Examples of the pre-definedlevel of platelet count include any number selected from 4×10⁴ to6×10⁴/μL. The pre-defined level of platelet count is preferably a numberselected from 4.5×10⁴ to 5.5×10⁴/μL, more preferably a number selectedfrom 4.8×10⁴ to 5.2×10⁴/μL, still more preferably a number selected from4.9×10⁴ to 5.1×10⁴/μL and most preferably 5×10⁴/μL.

The term “the pre-defined level of platelet count increment” in thepresent specification means a reference value that serves as a criterionas to how much increment from the platelet count before initiation ofadministration can be interpretered to indicate the tendency of increasein the platelet count in a patient who has a platelet count less thanthe pre-defined level of platelet count before invasive procedures whena compound having a thrombopoietin receptor agonistic activity isadministered to the patient. “2×10⁴/μL” used in the administrationdiscontinuating criteria is an embodiment of the “pre-defined level ofplatelet count increment”. The pre-defined level of platelet countincrement is any number selected from 1.5×10⁴ to 2.5×10⁴/μL, preferablya number selected from 1.8×10⁴ to 2.2×10⁴/μL, more preferably 1.9×10⁴ to2.1×10⁴/μL and still more preferably 2×10⁴/μL.

The term “invasive procedures” means procedures accompanied by bleeding.

The term “elective invasive procedures” means that, during the course ofa disease, invasive procedures are carried out when the timing issuitable. The elective invasive procedures include various invasiveprocedures, particularly various minimally invasive procedures. Examplesof minimally invasive procedures include local therapy, percutaneousneedle biopsy, puncture of abscess, transcatheter arterial embolization(TAE), hepatic arterial chemotherapy (Lip-TAI), trancecatheter arterialchemoembolization (TACE), laparoscopy, endoscopic variceal ligation(EVL), endoscopic injection sclerotherapy (EIS), endoscopy with possibletissue biopsy, endoscopic submucosal dissection (ESD), endoscopicmucosal resection (EMR), polypectomy, endoscopic retrograde biliarydrainage-expandable metallic stent (ERBD/EMS), endoscopic sphincterotomy(EST), percutaneous needle biopsy of organs (including endoscopicultrasound-guided fine-needle aspiration (EUS-FNA)), variousparacenteses, tooth extraction, transurethral resection of the prostate(TURP), transurethral resection of the bladder tumor (TUR-Bt),transurethral ureterolithotripsy (TUL), arthroscopy and the like.

Radiofrequency ablation (RFA) refers to a therapy in which coagulativenecrosis of a lesion site is induced by high temperature generated byradio waves (frequency of around 500 kHz).

Chronic liver disease is a disease in which hepatocytes are damaged bypersistent inflammation over a long period of time. Chronic liverdisease gradually develops into liver cirrhosis and, in some cases,liver cancer. Examples of chronic liver disease include chronic liverdisease caused by hepatitis B virus, chronic liver disease caused byhepatitis C virus, alcoholic chronic liver disease and non-alcoholicchronic steatohepatitis (NASH). In Japan, about 70% of chronic hepatitiscases are caused by hepatitis C and about 20% are caused by hepatitis B.

Examples of local therapy include therapies such as radiofrequencyablation (RFA), percutaneous ethanol injection therapy (PEIT) andmicrowave coagulation therapy (MCT).

The present invention is explained in more detail below by way ofExamples and Test Examples, but is not limited the following Examplesand Test Examples.

EXAMPLES Example 1 Prediction of Profile of a Platelet Count byMonte-Carlo Simulation

An excessive increase in the platelet count is considered to increase arisk of thrombosis. In order to ensure the safety of patients whoreceive drugs, we designed an administration discontinuating criteriabased on the platelet count. Using the data of pharmacokinetics andprofile of a platelet count from single administration and repeatedadministration trials of lusutrombopag carried out to healthy adults, aprofile of a platelet count during repeated administration oflusutrombopag for 7 days to chronic liver disease patients was predictedby Monte-Carlo simulation. In simulation, the PK/PD model parameters ofhealthy adults were estimated based on the data obtained from healthyadults (Test Example 1), and model parameters in chronic liver diseasepatients were calculated based on the PK/PD model in healthy adults(Test Example 2). Based on the calculated parameters, we verified thecriteria in which administration of lusutrombopag is discontinued at thetime point when the platelet count during administration period hasincreased by 2×10⁴/μL or more from the platelet count before initiationof administration and has reached to 5×10⁴/μL or higher (Test Example3).

Test Example 1

Using the plasma concentration of the drug and the platelet count dataof 54 cases obtained in phase 1 trial carried out in Japan to healthymale adults, a PK/PD model was constructed that can describepharmacokinetics and a profile of a platelet count. The PK modeldescribing pharmacokinetics was a three-compartment model includingthree compartments in the absorption process in order to explain thedelay in absorption. The PD model describing the relation between theplasma concentration and the profile of platelets counts was a modelincluding five compartments in order to explain the maturation processof platelets. FIG. 1 shows a schematic view of the PK/PD model with themass balance equation thereof. Table 1 shows the PK/PD model parametersestimated from the data obtained from healthy adults. We assumed thatthe distributions of respective model parameters and the distributionsof the residual errors of the models follow a log-normal distribution.Parameters were estimated by using the first order conditionalestimation method with interaction in a software NONMEM (version VI,level 2.0).

TABLE 1 Inter- Inter- individual individual PK variability PDvariability parameter Mean (%) parameter Mean (%) CL (L/hr) 0.776 17.6E_(max) 3.52 — V2/F (L) 15.9 × (1 + (BW − 18.0 EC₅₀ (ng/mL) 63) ×0.0172) Q3/F (L/hr) 0.946 — <50 mg/dose 64.7 50.0 V3/F (L) 6.28 — 50mg/dose 21.6 44.5 Q4/F (L/hr) 0.0262 — r 2.03 — V4/F (L) 2.71 — k_(m)(hr⁻¹) 0.0394 23.6 k_(tr) (hr⁻¹) k_(deg) (hr⁻¹) 0.00578 — Fasting + 4.1967.2 PLT₀ (×10⁴/ 20.1 16.1 solution μL) Postprandial + 2.15 53.1 γ 0.309— solution Postprandial + 1.38 41.8 Intra- 5.71 — tablet individualvariability (%) k_(a) (hr⁻¹) Fasting + 0.563 16.1 solutionPostprandial + 0.285 26.9 solution Postprandial + 0.854 — tablet Intra-12.1 — individual variability (%)

(Explanations of Table 1)

CL/F: Apparent total clearance. V2/F: Volume of distribution of thecentral compartment. V3/F and V4/F: Volumes of distribution ofperipheral compartments. Q3/F and Q4/F: Inter-compartmental clearances.k_(tr): Inter-absorption-compartmental transfer rate constant.

k_(a): Transfer rate constant from the absorption compartments to thecentral compartment.

E_(max), EC₅₀ and r: parameters of a sigmoid E_(max) model. k_(m):Inter-PD-compartmental transfer rate constant. k_(deg): Elimination rateconstant from the platelet compartment. PLT₀: Pre-defined level ofplatelet count. γ: Feedback coefficient.

BW: Body weight (kg).

-: Not estimated.

k_(a) and k_(tr): Predictions were made depending on combinations offeeding status and dosage forms.

EC₅₀: Estimation were made depending on the doses of less than 50mg/dose and 50 mg/dose.

Test Example 2 Estimation of PK/PD Parameters in Monte-Carlo Simulation

Based on the PK/PD model in healthy adults as described in (Test Example1), model parameters in chronic liver disease patients were estimated onthe basis of the following assumptions. Table 2 shows the estimatedPK/PD model parameters used for platelet count predictions in chronicliver disease patients.

(Assumptions Used for the Estimation)

-   -   PK parameters (CL, V2/F, Q2/F, V3/F, Q3/F, V4/F, Q4/F, k_(tr)        and k_(a)):        According to the results of phase 1 single administration        clinical trial to patients with hepatic disorder classified into        Child-Pugh classes A and B after administration of 0.75 mg of        lusutrombopag, pharmacokinetics of lusutrombopag in patients        with hepatic disorder were similar to those in healthy adults.        Therefore, as PK parameters those from healthy adults were used.        As parameters k_(a) and k_(tr), estimated values under the        conditions of postprandial and tablets were used in line with        clinical usage.    -   Pre-defined level of platelet count (PLT₀):        Based on the pre-defined level of platelet count expected in        chronic liver disease patients, the average and range of PLT₀        were set to 3×10⁴/μL and 2×10⁴ to 4.9×10⁴/μL, respectively.    -   Elimination rate constant from platelet compartment (k_(deg)):        It was reported that platelets destruction in chronic liver        disease patients was promoted (see Reference 1) and the survival        period of platelets was about ⅔ of that of healthy adults (see        References 2 and 3). Therefore, k_(deg), a parameter        representing the elimination rate of platelets, was set to the        value which was about 1.5 times of the value of healthy adults,        i.e. 0.009 hr⁻¹. In addition, based on the relationship that the        production rate of platelets is equal to the elimination rate of        platelets at baseline, k_(pr), a parameter representing the        production rate of platelets, was calculated from the formula:        PLT₀×k_(deg). As a result, k_(pr) was 0.027×10⁴/μL/hr which was        lower than the value in healthy adults (0.116×10⁴/μL/hr). This        estimated value matched the previous report that the production        rate of platelets was decreased in chronic liver disease        patients (see Reference 1).    -   Inter-PD-compartmental transfer rate constant (k_(m)):        It was assumed that a parameter k_(m) representing the        maturation rate of platelets in chronic liver disease patients        is similar to that in healthy adults. Therefore, the estimated        value in healthy adults was used as k_(m).    -   Parameters of a sigmoid E_(max) model (E_(max), EC₅₀ and r):        When the plasma concentration is sufficiently lower than EC₅₀        (EC₅₀>>C), the drug efficacy of lusutrombopag can be        approximated by E_(max)/EC₅₀. It was assumed based on the        clinical data of eltrombopag, a drug having the same efficacy        (see References 4 and 5) that E_(max)/EC₅₀ in this trial was        about 3 times of the value of healthy adults. It was also        assumed that the upper limit of platelets in the present model        (PLT₀×(1+E_(max))) in chronic liver disease patients was similar        to that in healthy adults and E_(max) was set to 29.3 and EC₅₀        to 180 ng/mL. Meanwhile, it was assumed that r in the patients        was similar to that in healthy adults. Therefore, the value in        healthy adults was used as r.    -   Feedback coefficient (γ):        A reduction in the production rate of platelets with an increase        in platelets, i.e the negative feedback phenomenon, is        represented by the formula (PLT₀/PLT)^(γ). It was assumed that        it is a unique phenomenon for healthy adults having a normal        platelet count level, and the negative feedback phenomenon does        not occur in chronic liver disease patients having a decreased        platelet baseline. Therefore, the negative feedback phenomenon        was not taken into account in the present simulation.    -   Body weight:        Body weight was assumed to follow normal distribution and the        average was set to 60 kg, the coefficient of variation was set        to 20%, and the range was set to 40 to 100 kg.    -   Inter-individual variability of PD model parameters:        As inter-individual variability of the respective PD parameters,        the values in healthy adults were used.    -   Intra-individual variability of plasma concentration and a        platelet count:        The intra-individual variability of plasma concentration was not        taken into account in the present simulation. As the        intra-individual variability of a platelet count, the value in        healthy adults was used.

REFERENCES

-   (Reference 1) Witters P, Freson K, Verslype C et al. Review article:    blood platelet number and function in chronic liver disease and    cirrhosis. Aliment Pharmacol Ther 2008; 27: 1017-1029.-   (Reference 2) Harker L A, Finch C A. Thrombokinetics in man. J Clin    Invest 1969; 48: 963-974.-   (Reference 3) Aoki Y, Hirai K, Tanikawa K. Mechanism of    thrombocytopenia in liver cirrhosis: kinetics of indium-111    tropolone labelled platelets. Eur J Nucl Med 1993; 20: 123-9.-   (Reference 4) FDA application material (application No.: NDA    22-291).-   (Reference 5) Data from GlaxoSimithKline (GSK study ID: 111913).

TABLE 2 Inter-individual Inter-individual PK variability PD variabilityparameter Mean (%) parameter Mean (%) CL (L/hr) 0.776 17.6 E_(max) 29.3— V2/F (L) 15.9 × (1 + (BW − 18.0 EC₅₀ (ng/mL) 180 50.0 63) × 0.0172)Q3/F (L/hr) 0.946 — r 2.03 — V3/F (L) 6.28 — k_(m) (hr⁻¹) 0.0394 23.6Q4/F (L/hr) 0.0262 — k_(deg) (hr⁻¹) 0.00900 — V4/F (L) 2.71 — PLT₀(×10⁴/ 3.00 16.1 μL) k_(tr) (hr⁻¹) 1.38 41.8 Intra- 5.71 individualvariability (%) k_(a) (hr⁻¹) 0.854 — —

(Explanations of Table 2)

-: Not estimated.

BW (body weight): Body weight was assumed to follow normal distributionand the average was set to 60 kg, the coefficient of variation was setto 20%, and the range was set to 40 to 100 kg.

PLT₀: In the simulation, the range was set to 2.0×10⁴ to 4.9×10⁴/μL.

Test Example 3

In order to develop a method for reducing the risk of portal veinthrombosis, Monte-Carlo simulation was used to predict the followingprofile based on the parameters estimated in (Test Example 2) describedabove;

a profile of a platelet count in chronic liver disease patientsrepeatedly receiving 2 mg of lusutrombopag once daily for 7 days, and

a profile of a platelet count in chronic liver disease patientsrepeatedly receiving 2 mg of lusutrombopag once daily for 7 days,provided that administration of lusutrombopag was discontinued at thetime point when, during administration period, the platelet count hasincreased by 2×10⁴/μL or more from a platelet count before initiation ofadministration and has reached to 5×10⁴/μL or higher.

Monte-Carlo simulation was carried out with Trial Simulator software(version 2.2.1). Table 3 shows the following proportions which werecalculated by the prediction;

the proportion of efficacy, i.e. the proportion of patients who had aplatelet count on day 8 after initiation of administration thatincreased by 2×10⁴/μL or more from a platelet count before initiation ofadministration and reached to 5×10⁴/μL or higher, and

the proportion of a thrombosis high-risk group, i.e. the proportion ofpatients who had the platelet count of higher than 20×10⁴/μL during theobservation period.

TABLE 3 Administration Proportion discontinuating of patientscriteria^(b)) Profile of platelet count (%) No Platelet count on day 8after initiation of 92.4 administration increased by 2 × 10⁴/μL or morefrom a platelet count before initiation of administration and reached to5 × 10⁴/μL or higher Platelet count during observation period exceeded35.8 20 × 10⁴/μL Yes Platelet count on day 8 after initiation of 92.5administration increased by 2 × 10⁴/μL or more from a platelet countbefore initiation of administration and reached to 5 × 10⁴/μL or higherPlatelet count during observation period exceeded 11.7 20 × 10⁴/μL

(Explanations of Table 3)

Administration: at 2 mg, once daily for 7 days.

a) The efficacy and safety was estimated with Monte-Carlo simulation bypredicting the platelet count over time of 1000 virtual patients withMonte-Carlo simulation and calculating the proportion of patients whohad a platelet count on day 8 after initiation of administration thatincreased by 2×10⁴/μL or more from a platelet count before initiation ofadministration and reached to 5×10⁴/μL or higher and the proportion ofpatients who had the platelet count of higher than 20×10⁴/μL during theobservation period (from initiation of administration to day 30 afterinitiation of administration).

b) Administration discontinuating criteria: Administration oflusutrombopag was discontinued at the time point when the platelet countduring administration has increased by 2×10⁴/μL or more from a plateletcount before initiation of administration and has reached to 5×10⁴/μL orhigher.

Without the administration discontinuating criteria, the estimatedproportion of patients who had the platelet count on day 8 afterinitiation of administration that increased by 2×10⁴/μL or more from aplatelet count before initiation of administration and reached to5×10⁴/μL or higher was 92.4%. The estimated proportion of patients whohad the platelet count of higher than 20×10⁴/μL during administrationperiod was 35.8%. On the other hand, with the administrationdiscontinuating criteria, the estimated proportion of patients who hadthe platelet count on day 8 after initiation of administration thatincreased by 2×10⁴/μL or more and reached to 5×10⁴/μL or higher was92.5% which was similar to the proportion without the discontinuationcriteria, while the estimated proportion of patients who had theplatelet count of higher than 20×10⁴/μL during observation period was11.7% which was lower than the proportion without the discontinuationcriteria. Thus, the present simulation shows that the administrationdiscontinuating criteria “administration of lusutrombopag isdiscontinued at the time point when the platelet count has increased by2×10⁴/μL or more from a platelet count before initiation ofadministration and has reached to 5×10⁴/μL or higher” can reduce theproportion of patients who had a platelet count of higher than 20×10⁴/μLwith almost no compromise on the efficacy, resulting in reduction of therisk of portal vein thrombosis.

Example 2 Test Example 1

To patients with thrombocytopenia caused by chronic liver disease,lusutrombopag as a pretreatment of percutaneous liver ablation wasorally administered repeatedly for 7 days while applying thediscontinuation criteria designed in Example 1 and profile of theplatelet count was studied. In the present Example, the term “ablation”refers to radiofrequency ablation.

(Target Disease)

Patients with thrombocytopenia caused by chronic liver disease who arescheduled to undergo percutaneous liver ablation.

(Inclusion Criteria)

Patients who meet the following inclusion criteria are included.

1) Age: 20 years of age or older (at the time of signing informedconsent);2) Patients who themselves can give a consent in writing;3) Patients who have a complication or a history of chronic liverdisease caused by hepatitis B or C virus;4) Patients who are scheduled to undergo percutaneous liver ablation forprimary liver cancer;5) Patients having a platelet count which is less than 5×10⁴/μL at thetime of screening;6) Patients whose ECOG* Performance Status of Grade is 0 to 1; and7) Patients who can practice contraception from entry to the end ofobservation.

(Exclusion Criteria)

Patients who meet the following criteria are excluded.

1) Patients who underwent splenectomy;2) Patients who have a complication presenting thrombocytopenia;3) Patients who underwent liver transplant;4) Degree of hepatic disorder classified as the Child-Pugh class of C;5) Hepatic encephalopathy uncontrolled by medicaments;6) Ascites uncontrolled by medicaments;7) Patients who have a complication of malignant tumor other thanprimary liver cancer;8) Patients who have a complication or a history of thrombosis orthrombotic disease;9) Patients who have absence of hepatopetal blood flow in the portalvein;10) Patients who have a complication or a history of disease withhemorrhage risk;11) Patients who received a therapeutic agent that affects a plateletcount or underwent a therapy that affects a platelet count within 90days before registry;12) Patients who received a blood product (excluding erythrocyteproduct) within 14 days before registry; or13) Patients who previously received a TPO receptor agonist.(Drugs which are Prohibited, Limited or Allowed for CoadministrationDuring the Trial)

Drugs (therapies) which are prohibited, limited or allowed forcoadministration during the trial are as follows:

(Drugs which are Prohibited for Coadministration)

The following drugs are prohibited from registry to the end ofobservation:

1) Blood products other than platelet and erythrocyte product such aswhole blood products, human immunoglobulin products, blood coagulationfactor products, fibrinogen, antithrombin III, fresh frozen plasma;2) Anti-cancer drugs;3) Interferon products;4) Colony stimulation factor (G-CSF, M-CSF) products;

5) Erythropoietin;

6) TPO receptor agonists;7) Antithrombotic drugs;8) Hemostatic drugs such as carbazochrome sodium sulfate;

9) Vitamin K; or

10) Other investigational drugs.

(Schedule)

In each allocated group, lusutrombopag is orally administered repeatedlyonce daily for 7 days. After patients are monitored on day 8, theyundergo percutaneous liver ablation before day 13 from initiation ofadministration. They are monitored until about day 30 after initiationof administration.

(Administration)

Lusutrombopag is orally administered repeatedly once daily for 7 days.On day 1, the drug is administered at the time of visit. On day 3 to day7 (day 5 to day 7 for the group of 2.0 mg administration), the drugshall be administered after checking the platelet count measured on thesame day. Administration of lusutrombopag shall be discontinued when theplatelet count reaches to the following criteria (administrationdiscontinuating criteria) in a clinical examination after administrationof the investigational drug.

Administration discontinuating criteria: when the platelet count hasincreased by 2×10⁴/μL or more from the platelet count before initiationof administration and the platelet count has reached to 5×10⁴/μL orhigher.

As the platelet count before initiation of administration, the plateletcount determined within 7 days before initiation of administration wasused.

(Dose)

Daily dose was any one of 2.0, 2.5, 3.0 and 4.0 mg of lusutrombopag.

(Endpoints) Endpoint 1

Proportion of patients who have a platelet count on day 8 afterinitiation of administration that increased by 2×10⁴/μL or more from theplatelet count before initiation of administration and reached to5×10⁴/μL or higher.

Endpoint 2

1) Proportion of patients who received platelet transfusion and thenumber and dose (units) of the transfusion;2) Proportion of patients who have a platelet count during theobservation period that increases by 2×10⁴/μL or more from the plateletcount before initiation of administration and reaches to 5×10⁴/μL orhigher;3) Platelet count;4) Number of adverse events relating to hemorrhage;5) Number of adverse events relating to thrombosis;6) Number of adverse events and side effects; and7) Plasma concentration of the unchanged drug.

(Results)

Data relating to the efficacy at each dose are shown in Table 4. Theprofile of the platelet count in each patient at the daily dose of 2.0mg, 2.5 mg, 3.0 mg and 4.0 mg of lusutrombopag is shown in FIGS. 2 to 5,respectively. It was confirmed that all doses showed the efficacy. Noneof the patients in any trials had a platelet count of higher than20×10⁴/μL during the observation period. Particularly, the patients inthe groups of the daily dose of 2 mg, 2.5 mg and 4.0 mg to whomadministration was discontinued according to the administrationdiscontinuating criteria of the present invention showed the following;“the platelet count increased over a certain period afterdiscontinuation of administration, and the maximum platelet count waslower than that of patients who received the drug for 7 days”. It isbelieved that by discontinuing administration of the drug according tothe administration discontinuating criteria of the present invention, anexcessive increase of platelets could be prevented. The results of thepresent trial demonstrated that the administration discontinuatingcriteria of the present invention is superior in that the criteria canensure the sufficient platelet count while preventing an excessiveincrease in the platelet count.

TABLE 4 Lusutrombopag (mg, once daily) 2.0 2.5 3.0 4.0 n = 12 n = 6 n =7 n = 8 Endpoint 1 Number (proportion, %) of 4 4 3 4 patients who had aplatelet (33.3) (66.7) (42.9) (50.0) count on day 8 after initiation ofadministration that increased by 2 × 10⁴/μL or more from the countbefore initiation of administration and reached to 5 × 10⁴/μL or higherEndpoint 2 Number (proportion, %) of 9 4 6 7 patients who had a platelet(75.0) (66.7) (85.7) (87.5) count during the trial that increased by 2 ×10⁴/μL or more from the count before initiation of administration andreached to 5 × 10⁴/μL or higher Number of patients who 2 1 1 1 receivedplatelet transfusion Discontinuation Number of patients to whom 3 3 0 2according to the administration was administration discontinuedaccording to the discontinuating administration criteria ^(a))discontinuating criteria Day(s) of 1 day 0 0 0 0 administration 2 days 00 0 1 3 days 0 0 0 0 4 days 0 0 0 1 5 days 2 1 0 0 6 days 1 2 0 0

(Explanations of Table 4)

a) Administration discontinuating criteria: Administration oflusutrombopag was discontinued at the time point when the platelet countduring administration period has increased by 2×10⁴/μL or more from theplatelet count before initiation of administration and has reached to5×10⁴/μL or higher.

Test Example 2

To patients with thrombocytopenia caused by chronic liver disease,lusutrombopag as a pretreatment of percutaneous liver ablation wasorally administered repeatedly for 7 days while applying thediscontinuation criteria designed in Example 1 and profile of theplatelet count was studied. In the present Example, the term “ablation”refers to radiofrequency ablation.

(Target Disease)

Patients with thrombocytopenia caused by chronic liver disease who arescheduled to undergo percutaneous liver ablation.

(Inclusion Criteria)

Patients who meet the following inclusion criteria are included.

1) Age: 20 years of age or older (at the time of consent);2) Patients who themselves can give a consent in writing;3) Patients with thrombocytopenia caused by chronic liver disease;4) Patients who are scheduled to undergo percutaneous liver ablation forprimary liver cancer;5) Patients having a platelet count which is less than 5×10⁴/μL at thetime of screening;6) Patients whose ECOG* Performance Status of Grade is 0 to 1; and7) Patients who can practice contraception from entry to the end ofobservation.

(Exclusion Criteria)

Patients who meet the following criteria are excluded.

1) Patients who underwent splenectomy;2) Patients who have a complication presenting thrombocytopenia;3) Patients who underwent liver transplant;4) Degree of hepatic disorder classified as the Child-Pugh class of C;5) Hepatic encephalopathy uncontrolled by medicaments;6) Ascites uncontrolled by medicaments;7) Patients who have a complication of malignant tumor other thanprimary liver cancer;8) Patients who have a complication or a history of thrombosis orthrombotic disease;9) Patients who have absence of hepatopetal blood flow in the portalvein;10) Patients who have a complication or a history of disease withhemorrhage risk;11) Patients who received a therapeutic agent that affects a plateletcount or underwent a therapy that affects a platelet count within 90days before registry;12) Patients who received a blood product (excluding erythrocyteproduct) within 14 days before registry; or13) Patients who previously received a TPO receptor agonist.(Drugs which are Prohibited, Limited or Allowed for CoadministrationDuring the Trial)

Drugs (therapies) which are prohibited, limited or allowed forcoadministration during the trial are as follows:

(Drugs which are Prohibited for Coadministration)

The following drugs are prohibited from registry to the end ofobservation:

1) Blood products other than platelet and erythrocyte products such aswhole blood products, human immunoglobulin products, blood coagulationfactor products, fibrinogen, antithrombin III, fresh frozen plasma;2) Anti-cancer drugs;3) Interferon products;4) Colony stimulation factor (G-CSF, M-CSF) products;

5) Erythropoietin;

6) TPO receptor agonists;7) Antithrombotic drugs;8) Hemostatic drugs such as carbazochrome sodium sulfate;

9) Vitamin K; or

10) Other investigational drugs.

(Schedule)

In each allocated group, lusutrombopag is orally administered repeatedlyonce daily for 7 days. After patients are monitored on day 8, theyundergo percutaneous liver ablation before day 14 from initiation ofadministration. They are monitored until about day 30 after initiationof administration.

(Administration)

Lusutrombopag is orally administered repeatedly once daily for 7 days.On day 1, the drug is administered at the time of visit. On day 5 to day7, the drug shall be administered after checking the platelet countmeasured on the same day. Administration of lusutrombopag shall bediscontinued when the platelet count reaches to the following criteria(administration discontinuating criteria) in a clinical examinationafter administration of the investigational drug.

Administration discontinuating criteria: when the platelet count hasincreased by 2×10⁴/μL or more from the platelet count before initiationof administration and the platelet count has reached to 5×10⁴/μL orhigher.

As the platelet count before initiation of administration, the plateletcount determined within 7 days before initiation of administration wasused.

(Dose)

Daily dose was any one of 2.0, 3.0 and 4.0 mg of lusutrombopag.

(Endpoints) Endpoint 1

Proportion of patients who have a platelet count on day 8 afterinitiation of administration that increased by 2×10⁴/μL or more from aplatelet count before initiation of administration and reached to5×10⁴/μL or higher.

Endpoint 2

1) Proportion of patients who received platelet transfusion and thenumber and dose (units) of the transfusion;2) Proportion of patients who have a platelet count during theobservation period that increases by 2×10⁴/μL or more from the plateletcount before initiation of administration and reaches to 5×10⁴/μL orhigher;3) Platelet count;4) Number of adverse events relating to hemorrhage;5) Number of adverse events relating to thrombosis;6) Number of adverse events and side effects; and7) Plasma concentration of the unchanged drug.

(Results)

Data relating to the efficacy at each dose are shown in Table 5. It wasconfirmed that all doses showed the efficacy. None of the patients inany trials had a platelet count of higher than 20×10⁴/μL during theobservation period. The results of the present trial demonstrated thatthe administration discontinuating criteria of the present invention issuperior in that the criteria can ensure the sufficient platelet countwhile preventing an excessive increase in the platelet count.

TABLE 5 Lusutrombopag (mg, once daily) Placebo 2.0 3.0 4.0 n = 15 n = 15n = 16 n = 15 Endpoint 1 Number (proportion, %) of 0 6 5 8 patients whohad a platelet (0.0) (40.0) (33.3) (53.3) count on day 8 afterinitiation of administration that increased by 2 × 10⁴/μL or more fromthe count before initiation of administration and reached to 5 × 10⁴/μLor higher Endpoint 2 Number (proportion, %) of 1 10 11 12 patients whohad a platelet (6.7) (66.7) (68.8) (80.0) count during the trial thatincreased by 2 × 10⁴/μL or more from the count before initiation ofadministration and reached to 5 × 10⁴/μL or higher Number of patientswho 12 3 3 4 received platelet transfusion Discontinuation Number ofpatients to whom 0 3 3 5 according to the administration wasadministration discontinued according to the discontinuatingadministration criteria ^(a)) discontinuating criteria Day(s) of 1 day 00 0 0 administration 2 days 0 0 0 0 3 days 0 0 0 0 4 days 0 0 1 1 5 days0 1 2 0 6 days 0 2 0 4

(Explanations of Table 5)

a) Administration discontinuating criteria: Administration oflusutrombopag was discontinued at the time point when the platelet countduring administration period has increased by 2×10⁴/μL or more from theplatelet count before initiation of administration and has reached to5×10⁴/μL or higher.

Formulation Examples

The following Formulation Examples are only exemplified and not intendedto limit the scope of the invention.

Formulation Example 1 Tablets

Compound of the present invention 15 mg Lactose 15 mg Calcium stearate 3 mg

The components other than calcium stearate are homogeneously mixed, andthe mixture is ground, granulated and dried to obtain an appropriatesize of granules. Then, calcium stearate is added thereto and themixture is compressed to obtain tablets.

Formulation Example 2 Capsules

Compound of the present invention 10 mg Magnesium stearate 10 mg Lactose80 mg

The above components are homogeneously mixed to obtain powder or finegranules. Then, the powder medicines are encapsulated in capsule shellsto obtain capsules.

Formulation Example 3 Granules

Compound of the present invention  30 g Lactose 265 g Maanesium stearate 5 g

The above components are thoroughly mixed, and the mixture is compressedand molded. Then, it is ground, granulated and sieved to obtain anappropriate size of granules.

INDUSTRIAL APPLICABILITY

It is believed that the pharmaceutical composition having athrombopoietin receptor agonistic activity according to the presentinvention is useful because it can increase platelets while avoiding arisk of thrombosis caused by an excessive increase in the plateletcount.

1. A pharmaceutical composition for increasing platelets containing acompound having a thrombopoietin receptor agonistic activity,characterized by discontinuing administration of the pharmaceuticalcomposition to a patient at the time point when a platelet count in thepatient has increased by 2×10⁴/μL or more from a platelet count beforeinitiation of administration and has reached to 5×10⁴/μL or higher. 2.The pharmaceutical composition according to claim 1, which isadministered to a thrombocytopenia patient.
 3. The pharmaceuticalcomposition according to claim 1, wherein the platelet count in thepatient before initiation of administration of the pharmaceuticalcomposition is less than 5×10⁴/μL.
 4. The pharmaceutical compositionaccording to claim 2, wherein the patient is scheduled to undergoinvasive procedures.
 5. The pharmaceutical composition according toclaim 4, wherein the invasive procedures are elective invasiveprocedures.
 6. The pharmaceutical composition according to claim 4,wherein the invasive procedures are radiofrequency ablation.
 7. Thepharmaceutical composition according to claim 6, wherein theradiofrequency ablation is performed on liver cancer.
 8. Thepharmaceutical composition according to claim 7, wherein the livercancer is primary liver cancer.
 9. The pharmaceutical compositionaccording to claim 1, wherein the patient has chronic liver disease. 10.The pharmaceutical composition according to claim 9, wherein the chronicliver disease is caused by hepatitis B virus or hepatitis C virus. 11.The pharmaceutical composition according to claim 1, wherein thecompound having a thrombopoietin receptor agonistic activity is(E)-3-[2,6-dichloro-4-[4-[3-[(S)-1-hexyloxyethyl]-2-methoxyphenyl]-thiazol-2-ylcarbamoyl]-phenyl]-2-methylacrylicacid or a salt thereof.
 12. The pharmaceutical composition according toclaim 11, which is orally administered.
 13. The pharmaceuticalcomposition according to claim 12, which is administered at 2.0 to 4.0mg/day as an amount of(E)-3-[2,6-dichloro-4-[4-[3-[(S)-1-hexyloxyethyl]-2-methoxyphenyl]-thiazol-2-ylcarbamoyl]-phenyl]-2-methylacrylicacid or a salt thereof.
 14. The pharmaceutical composition according toclaim 13, wherein a maximum administration period with once dailyadministration is 14 days or less.
 15. The pharmaceutical compositionaccording to claim 1, for promoting production of platelets beforeinvasive procedures in thrombocytopenic patients with chronic liverdisease.
 16. The pharmaceutical composition according to claim 1, forpromoting production of platelets before elective invasive procedures inthrombocytopenic patients with chronic liver disease.
 17. Thepharmaceutical composition according to claim 1, for promotingproduction of platelets before local therapy for primary liver cancer.18. The pharmaceutical composition according to claim 1, for promotingproduction of platelets before radiofrequency ablation for primary livercancer.
 19. The pharmaceutical composition according to claim 1, forpromoting production of platelets before various minimally invasiveprocedures in thrombocytopenic patients with chronic liver disease. 20.A method for increasing platelets comprising the steps of: administeringa pharmaceutical composition containing a compound having athrombopoietin receptor agonistic activity to a patient; anddiscontinuing administration at the time point when a platelet count inthe patient has increased by 2×10⁴/μL or more from a platelet countbefore initiation of administration and has reached to 5×10⁴/μL orhigher.
 21. A compound having a thrombopoietin receptor agonisticactivity for use in increasing platelets, characterized by discontinuingadministration of the compound to a patient at the time point when aplatelet count in the patient has increased by 2×10⁴/μL or more from aplatelet count before initiation of administration and has reached to5×10⁴/μL or higher.
 22. Use of a compound having a thrombopoietinreceptor agonistic activity for manufacturing a medicament forincreasing platelets, characterized by discontinuing administration ofthe medicament to a patient at the time point when a platelet count inthe patient has increased by 2×10⁴/μL or more from a platelet countbefore initiation of administration and has reached to 5×10⁴/μL orhigher.